title: Increased tumor necrosis factor-alpha (TNF-alpha) gene expression in parainfluenza type 1 (Sendai) virus-induced bronchiolar fibrosis.
abstract: Increased airway resistance and airway hyperresponsiveness induced in rats by infection with parainfluenza type I (Sendai) virus is associated with bronchiolar fibrosis. To determine whether increased tumor necrosis factor (TNF)-alpha gene expression is an important regulatory event in virus-induced bronchiolar fibrosis, pulmonary TNF-alpha mRNA and protein expression was assessed in rat strains that are susceptible (Brown Norway; BN) and resistant (Fischer 344; F344) to virus-induced bronchiolar fibrosis. Virus-inoculated BN rats had increased TNF-alpha pulmonary mRNA levels (P < 0.05) and increased numbers of bronchiolar macrophages and fibroblasts expressing TNF-alpha protein compared with virus-inoculated F344 rats (P < 0.05). Virus inoculation also induced elevated TNF-alpha mRNA and protein levels (P < 0.05) in cultured rat alveolar macrophages (NR8383 cells). A 55-kd soluble TNF receptor-immunoglobulin G fusion protein (sTNFR-IgG) was used to inhibit TNF-alpha bioactivity in virus-inoculated BN rats. Treated rats had fewer proliferating bronchiolar fibroblasts, as detected by bromodeoxyuridine incorporation, compared with virus-inoculated control rats (P < 0.05). There was also increased mortality in p55sTNFR-IgG-treated virus-inoculated rats associated with increased viral replication and decreased numbers of macrophages and lymphocytes in bronchoalveolar lavage fluid (P < 0.05). The results of this study indicate that 1) Sendai virus can directly up-regulate TNF-alpha mRNA and protein expression in macrophages, 2) TNF-alpha is an important mediator of virus-induced bronchiolar fibrosis, and 3) TNF-alpha has a critical role in the termination of Sendai viral replication in the lung.
authors.affiliation: Department of Pathobiology, University of Florida, Gainesville 32610-0145, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Uhl
authors.forename: L L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: W W
authors.initials: WW
authors.lastname: Busse
authors.forename: T J
authors.initials: TJ
authors.lastname: Jack
authors.forename: W L
authors.initials: WL
authors.lastname: Castleman
mesh_terms: D000818:Animals; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression / Q000502:physiology*; D007074:Immunoglobulin G / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D018108:Respirovirus / Q000302:isolation & purification; D010253:Respirovirus Infections / Q000150:complications* / Q000235:genetics / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha